The mechanisms contributing to the pathogenesis of rheumatoid arthritis (RA) are incompletely understood. Among the genetic markers associated with RA, FLIP has recently been identified as a RA risk allele. FLIP is important in preventing death receptor mediated apoptosis and has been shown to be critical to protect dendritic cells (DCs) and macrophages from Fas-mediated cell death. We recently examined the in vivo role of Flip in CD11c-expressing cells such as cells DCs and a subset of macrophages, by deleting Flip in CD11c+ cells generating CD11c-Flip-KO or HUPO mice. HUPO mice develop spontaneous, inflammatory, erosive arthritis, associated with autoantibodies to constituents of the synovial joints, resembling RA. A number of observations suggest that the insights derived from the HUPO mouse will inform our understanding of the pathogenesis of RA. As observed in patients with RA, the HUPO mice are mildly lymphopenic. Further patients with RA exhibit reduced Treg activity within the joints and the number of circulating Tregs may be reduced, inversely correlating with disease activity. HUPO mice exhibit a reduction of thymocytes available for emigration to the periphery, and patients with RA demonstrate a deficiency of recent thymic emigrants, which are important for the generation of Tregs in the periphery. As in HUPO mice, Flt3L is increased in patients with RA, suggesting a relative reduction of DCs in patients with RA. Based on the data, it is clear that HUPO arthritis is mediated by a complex mechanism, and that defining the mechanisms responsible for the initiation and progression of HUPO arthritis will provide insights into the pathogenesis of RA. Based on preliminary data, we propose the novel hypothesis that a reduction of CD11c+ synovial tissue- resident macrophages is critical for initiating the arthritis in HUPO mice. Reduction, but not absence of Tregs permits expansion of autoreactive T cells and autoantibodies directed against cartilage autoantigens released due to macrophage-mediated inflammation, which together promote disease progression. Further, we hypothesize that the reduction of the percent of Tregs is mediated by diminished CD8?+ DCs and decreased basal IL-2. This hypothesis will be tested with 3 specific aims: 1) Define the role of innate immunity in HUPO mice identifying the role of circulating monocytes, tissue- resident macrophages and monocyte derived macrophages in the initiation and progression of arthritis. 2) Define the adaptive immune mechanisms responsible for the initiation and/or progression of disease employing mice deficient in T cells or B cells, defining the association of T cell autoreactivity, autoantigen- specific T cells and autoantibodies to joint constituents with the clinical course of the arthritis. 3) Define the mechanisms responsible for the reduction of Tregs in HUPO mice, and identify therapeutic approaches that will increase Tregs and prevent or ameliorate the arthritis.